Without limiting the scope of the invention, its background is described in connection with existing tumor treatments.
Given that tumor cells are derived from normal cells and share basic metabolic features with the normal cells from which they are derived, selective destruction of tumor cells is in most cases a balance between relative toxicity to tumor versus normal cells. While the successful treatment of certain cancers has come within reach, tumors such as for example glioblastoma and pancreatic cancer remain particularly difficult to treat and are typically associated with a dire prognosis.
Indeed, pancreatic cancer is one of the most lethal of gastrointestinal malignancies. Pancreatic cancer is the fourth most frequent cause of cancer-related deaths in North America, the sixth in Europe, and the fifth in the UK. The disease is highly resistant to currently available treatments. Surgical resection provides the best possibility for long-term survival, but is feasible in a minority of patients only and is not without risk. In advanced disease where surgery is not an option, chemotherapy comes into play, using in particular gemcitabine or 5-FU (5-fluorouracil), although the effects are still modest and always accompanied by high general toxicity. Malignant glioma is another one of the highly lethal human cancers. With conventional treatment of surgery, radiation and chemotherapy, the average life span after diagnosis is 12-16 months.
Cancer therapy using viruses or armed vector derivatives that specifically kill neoplastically transformed cells (oncolysis) is a novel approach to the treatment of certain cancers. Oncolytic viruses, which by definition preferentially infect and/or kill cancer cells, include certain members of a number of the virus families including herpesviridae (i.e. HSV, CMV and pseudorabies), poxviridae, adenoviridae, parvoviridae, rhabdoviridae (i.e. vesicular stomatitis virus), togaviridae (Sindbis) and picornaviridae (i.e. coxsackie virus and poliovirus).
A recent therapy for pancreatic cancer and other carcinomas has included delivery of an adenovirus that is selectively oncolytic for TP-53 deficient pancreatic tumor cells. See Hecht J R, et al. “A phase I/II trial of intratumoral endoscopic ultrasound injection of ONYX-015 with intravenous gemcitabine in unresectable pancreatic carcinoma.” Clin Cancer Res 9 (2003) 555-61. A phase II trial of intralesional administration of ONYX-015 for treatment of hepatobiliary carcinoma has also been undertaken and showed the treatment to be safe and well tolerated with modest evidence of clinical benefit. See Malkower D. et al. “Phase II Clinical Trial of Intralesional Administration of the Oncolytic Adenovirus ONYX-015 in Patients with Hepatobiliary Tumors with Correlative p53 Studies” Clinical Cancer Research 9 (2003) 693. In 2005, Shanghai Sunway Biotech's genetically modified adenovirus H101, which is closely related to ONYX-015, became the first oncolytic virus to be approved by a regulatory agency for the treatment of head and neck cancer.
Human glioblastoma tumor cell lines have been found to be particularly susceptible to infection by oncolytic parvoviruses. Treatment of human gliomas with such parvoviruses by local intratumoral delivery via steriotactic surgical injection, neuronavigation targeting, and by placement of an implanted catheter connected to a low flow pump has been suggested. See Rommelaere et al U.S. Pat. No. 7,179,456. Other viruses shown to be particularly active against glioblastomas include Vesicular Stomatitis Virus (VSV) and Sindbis virus. See Wollman et al. Targeting Human Glioblastoma Cells: Comparison of Nine Viruses with Oncolytic Potential. J. Virol. 79 (10) (2005) 6005-6022.
Despite the impressive results achieved with oncolytic agents, the anticancer effects of such agents could be improved, particularly as to routes of administration.